U.S. patent application number 14/571714 was filed with the patent office on 2015-04-02 for process for the preparation of morphine analogs via metal catalyzed n-demethylation/functionalization and intramolecular group transfer.
The applicant listed for this patent is Brock University. Invention is credited to Tomas Hudlicky, Ales Machara.
Application Number | 20150094471 14/571714 |
Document ID | / |
Family ID | 47090667 |
Filed Date | 2015-04-02 |
United States Patent
Application |
20150094471 |
Kind Code |
A1 |
Hudlicky; Tomas ; et
al. |
April 2, 2015 |
PROCESS FOR THE PREPARATION OF MORPHINE ANALOGS VIA METAL CATALYZED
N-DEMETHYLATION/FUNCTIONALIZATION AND INTRAMOLECULAR GROUP
TRANSFER
Abstract
The present application is directed to an efficient conversion
of C-14 hydroxylated morphine alkaloids to various morphine
analogs, such as naltrexone, naloxone and nalbuphone. One feature
of this process is an intramolecular functional group transfer from
the C-14 hydroxyl to the N-17 nitrogen atom following a
palladium-catalyzed N-demethylation.
Inventors: |
Hudlicky; Tomas; (St.
Catharines, CA) ; Machara; Ales; (Brevnov,
CZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Brock University |
St. Catharines |
|
CA |
|
|
Family ID: |
47090667 |
Appl. No.: |
14/571714 |
Filed: |
December 16, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13464247 |
May 4, 2012 |
8946214 |
|
|
14571714 |
|
|
|
|
61483264 |
May 6, 2011 |
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Current U.S.
Class: |
546/45 ;
546/44 |
Current CPC
Class: |
C07D 489/02 20130101;
C07D 489/08 20130101; A61P 29/00 20180101; A61P 25/04 20180101 |
Class at
Publication: |
546/45 ;
546/44 |
International
Class: |
C07D 489/02 20060101
C07D489/02 |
Claims
1. A process for the preparation of a compound of Formula I:
##STR00024## comprising: (a) reacting a compound of Formula II with
a compound of Formula IIIa or IIIb under conditions to provide a
compound of Formula IV: ##STR00025## (b) reacting the compound of
Formula IV with a metal catalyst in the presence of an oxidant
under conditions to provide a compound of Formula V: ##STR00026##
(c) treating the compound of Formula V with a reducing agent under
conditions to provide the compound of Formula I, wherein each
R.sup.1 is selected from C.sub.3-10cycloalkyl, C.sub.1-10alkyl and
C.sub.6-10aryl, and each LG is a leaving group; wherein in the
compounds of the Formulae I, III, IV and V, one or more available
hydrogens in R.sup.1 is/are optionally replaced with F and/or one
or more of available atoms in R.sup.1 is/are optionally replaced
with an isotopic label.
2. The process of claim 1, wherein R.sup.1 is selected from
C.sub.3-6cycloalkyl, C.sub.1-6alkyl, and phenyl.
3. The process of claim 2, wherein R.sup.1 is selected from
cyclopropyl, cyclobutyl, cyclopentyl, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, t-butyl and phenyl.
4. The process of claim 3, wherein R.sup.1 is selected from
cyclopropyl and cyclobutyl, and the compound of Formula I is
naltrexone or nalbuphone, respectively.
5. The process of claim 1, wherein LG is halo or
O--C(O)R.sup.1.
6. The process of claim 1, wherein the metal catalyst is a catalyst
comprising palladium, platinum, ruthenium, iron, tungsten,
vanadium, copper, gold, and silver complexes.
7. The process of claim 6, wherein the palladium catalyst is a
Pd(0) or Pd(II) catalyst.
8. The process of claim 7, wherein the Pd(0) or Pd(II) catalyst, is
Pd(OAc).sub.2, Pd(acac).sub.2, Pd black or Pd-pervoskites, and the
Pd catalyst is optionally supported on a solid support or is in
encapsulated form.
9. The process of claim 1 wherein the conditions to provide a
compound of Formula IV comprise combining the compound of Formula
II with the compound of Formula IIIa or IIIb in the presence of a
non-nucleophilic base in an inert solvent.
10. The process of claim 1, wherein (b) is carried out in the
presence of a co-catalyst.
11. The process of claim 10, wherein the co-catalyst is a copper
salt or a cerium salt.
12. The process of claim 1, wherein (b) carried out in the presence
of an oxidant.
13. The process of claim 12, wherein the oxidant is selected
O.sub.2 gas, an oxidant, and an air atmosphere.
14. The process of claim 1, wherein (b) is carried out in aqueous
solutions or in an inert solvent or a mixture of solvents selected
from dioxane, toluene, benzene, DMF, C.sub.1-6alkylOH,
acetonitrile, diethylcarbonate, ionic liquids, water, dilute
aqueous acid and dilute aqueous base.
15. The process of claim 1, wherein the reducing agent in (c) is a
metal hydride reducing agent.
16. The process of claim 15, wherein the metal hydride reducing
agent is lithium aluminum hydride or sodium
bis(2-methoxyethoxy)aluminum hydride.
17. A compound of Formula IV or V: ##STR00027## wherein R.sup.1 is,
independently, selected from C.sub.3-10cycloalkyl, C.sub.1-10alkyl
and C.sub.6-10aryl.
18. The compound of claim 17, wherein R.sup.1 in the compound of
Formula IV or V is, independently selected from
C.sub.3-6cycloalkyl, C.sub.1-6alkyl and phenyl.
19. The compound of claim 18, wherein R.sup.1 in the compound of
Formula IV or V is, independently selected from cyclopropyl,
cyclobutyl, cyclopentyl, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl and phenyl.
20. The compound of claim 19, wherein R.sup.1 in the compound of
Formula IV or V is, independently selected from cyclopropyl and
cyclobutyl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional patent application
of co-pending patent application Ser. No. 13/464,247 filed on May
4, 2012 which claims the benefit of priority from U.S. provisional
application No. 61/483,264 filed on May 6, 2011, the contents of
both of which are incorporated herein by reference in their
entirety.
FIELD OF THE APPLICATION
[0002] The present application relates to an efficient
N-demethylation/functionalization/reduction sequence for C-14
hydroxylated morphine alkaloids such as, oxymorphone, in particular
for the preparation of various morphine analogs such as naltrexone,
naloxone and nalbuphone.
BACKGROUND OF THE APPLICATION
[0003] The synthesis of all opiate-derived analgesic agents as well
as the various antagonists or mixed agonists currently used in
medicine originates in naturally occurring alkaloids isolated from
the opium poppy latex. The most commonly used are morphine and its
congeners codeine, thebaine, and oripavine, shown in Scheme 1.
##STR00001##
[0004] There are two major challenges in the large scale
manufacture of the ubiquitously used pharmaceutical agents such as
oxycodone, oxymorphone, naltrexone, naloxone, and nalbuphone, also
shown in Scheme 1.
[0005] The first of the two challenges, the introduction of the
C-14 hydroxyl represents an important step in the manufacture of
all of these compounds. Nevertheless, this problem has been
adequately solved by various oxidation protocols and thebaine and
oripavine lend themselves as especially convenient starting
materials for the C-14 hydroxylated analogs. Thus one would not
expect that much improvement could be incorporated into the
manufacturing process save for completely new methods involving
C--H activation or biological catalysis. The second challenge, and
a much more difficult one, rests in the formal exchange of the
N-methyl group of natural opiates for the N-cyclopropylmethyl,
N-allyl, or N-cyclobutylmethyl functionality found in naltrexone,
naloxone, and nalbuphone, respectively.
[0006] The N-demethylation protocols previously reported include
the von Braun reaction employing cyanogen bromide.sup.i,
chloroformate reagents.sup.ii, photochemical methods.sup.iii,
demethylation of N-oxides.sup.iv, as well as microbial.sup.v and
enzymatic.sup.vi methods. The secondary amines are then converted
to the corresponding products by alkylation.
N-Demethylation/acylation of hydrocodone and tropane alkaloids was
also accomplished via palladium catalysts that provided
N-acetylhydrocodone and other acyl derivatives..sup.vii
SUMMARY OF THE APPLICATION
[0007] As it appears likely that the synthesis of oxymorphone from
oripavine or thebaine proceeds efficiently on industrial scale, the
present application relates to the efficient conversion of C-14
hydroxy morphone alkaloids, such as oxymorphone, to various
morphine analogs, such as naltrexone, naloxone and nalbuphone, in a
direct way. For example, oxymorphone was transformed in three
chemical steps and 75% overall yield to naltrexone. The features of
this process involve intramolecular acyl transfer from the C-14
hydroxyl to the nitrogen atom following metal-catalyzed
N-demethylation. In one embodiment of the process, the
cyclopropylcarboxamide was then reduced, along with the ester
protecting groups at C-3 and C-6.
[0008] Accordingly, the present application includes a process for
the preparation of a compound of Formula I:
##STR00002##
the process comprising: (a) reacting a compound of Formula II with
a compound of Formula IIIa or IIIb under conditions to provide a
compound of Formula IV:
##STR00003##
(b) reacting the compound of Formula IV with a metal catalyst in
the presence of an oxidant under conditions to provide a compound
of Formula V:
##STR00004##
and (c) treating the compound of Formula V with a reducing agent
under conditions to provide the compound of Formula I, wherein each
R.sup.1 is selected from C.sub.3-10cycloalkyl, C.sub.1-10alkyl, and
C.sub.6-10aryl, and LG is a leaving group; and wherein in the
compounds of the Formulae I, III, IV and V, one or more available
hydrogens in R.sup.1 is/are optionally replaced with F and/or one
or more of available atoms in R.sup.1 is/are optionally replaced
with an isotopic label.
[0009] The process of the present application can also include the
transfer of other functional groups from the C-14 hydroxyl group to
N-17 on other morphine analogs. Therefore, the present application
also includes a process for the preparation of a compound of
Formula VI:
##STR00005##
wherein X is selected from C(O)R.sup.2, S(O)R.sup.2,
SO.sub.2R.sup.2, P(O)R.sup.2R.sup.2', P(O)(OR.sup.2)R.sup.2' and
P(O)(OR.sup.2)(OR.sup.2'); R.sup.2 and R.sup.2' are independently
selected from C.sub.3-10cycloalkyl, C.sub.3-10heterocycloalkyl,
C.sub.3-10cycloalkenyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.6-10aryl and C.sub.5-10heteroaryl, each of the latter groups
being unsubstituted or substituted with one or more substituents
independently selected from C.sub.1-4alkyl, OC.sub.1-4alkyl, halo,
CN, NO.sub.2, C.sub.6-10aryl and OC.sub.6-10aryl; represents a
single or double bond, provided that two double bonds are not
adjacent to each other; and R.sup.3 and R.sup.4 are independently
selected from C.sub.1-10alkyl, C.sub.6-10aryl,
C.sub.3-10cycloalkyl, C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG, except when
represents .dbd.O, then R.sup.4 is not present; the process
comprising: (a) reacting a compound of Formula VII with a compound
of Formula VIII(a) or VIII(b) under conditions to provide a
compound of Formula IX:
##STR00006##
wherein LG.sup.1 is a leaving group; X is selected from
C(O)R.sup.2, S(O)R.sup.2, SO.sub.2R.sup.2, P(O)R.sup.2R.sup.2',
P(O)(OR.sup.2)R.sup.2' and P(O)(OR.sup.2)(OR.sup.2'); R.sup.2 and
R.sup.2' are independently selected from C.sub.3-10cycloalkyl,
C.sub.3-10heterocycloalkyl, C.sub.3-10cycloalkenyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.6-10aryl and
C.sub.5-10heteroaryl, each of the latter groups being unsubstituted
or substituted with one or more substituents independently selected
from C.sub.1-4alkyl, OC.sub.1-4alkyl, halo, CN, NO.sub.2,
C.sub.6-10aryl and OC.sub.6-10aryl; represents a single or double
bond, provided that two double bonds are not adjacent to each
other; and R.sup.3 and R.sup.4 are independently selected from
C.sub.1-10alkyl, C.sub.6-10aryl, C.sub.3-10cycloalkyl,
C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG, except when
represents .dbd.O, then R.sup.4 is not present; and (b) reacting
the compound of Formula IX with a metal catalyst in the presence of
an oxidant under conditions to provide the compound of Formula VI,
wherein in the compounds of Formulae VI, VII, VIII and IX, one or
more available hydrogens in R.sup.2, R.sup.2', R.sup.3 and R.sup.4
is/are optionally replaced with F and/or one or more of available
atoms in R.sup.2, R.sup.2', R.sup.3 and R.sup.4 is/are optionally
replaced with an isotopic label.
[0010] In an embodiment, the compound of Formula VI is selected
from a compound of Formula VI(a), VI(b) and VI(c):
##STR00007##
wherein X is selected from C(O)R.sup.2, S(O)R.sup.2,
SO.sub.2R.sup.2, P(O)R.sup.2R.sup.2', P(O)(OR.sup.2)R.sup.2' and
P(O)(OR.sup.2)(OR.sup.2'); R.sup.2 and R.sup.2' are independently
selected from C.sub.3-10cycloalkyl, C.sub.3-10heterocycloalkyl,
C.sub.3-10cycloalkenyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.6-10aryl and C.sub.5-10heteroaryl, each of the latter groups
being unsubstituted or substituted with one or more substituents
independently selected from C.sub.1-4alkyl, OC.sub.1-4alkyl, halo,
CN, NO.sub.2, C.sub.6-10aryl and OC.sub.6-10aryl; represents a
single or double bond; R.sup.3 and R.sup.4 are independently
selected from C.sub.1-10alkyl, C.sub.6-10aryl,
C.sub.3-10cycloalkyl, C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG, and one or more
available hydrogens in R.sup.2, R.sup.2', R.sup.3 and R.sup.4
is/are optionally replaced with F and/or one or more of available
atoms in R.sup.2, R.sup.2', R.sup.3 and R.sup.4 is/are optionally
replaced with an isotopic label.
[0011] The compounds of Formula VI are useful intermediates in the
preparation of morphine alkaloids. For example, in one embodiment,
the X group may be selectively removed, via acid or base
hydrolysis, from N-17, to provide the corresponding secondary amine
of Formula X:
##STR00008##
wherein represents a single or double bond, provided that two
double bonds are not adjacent to each other; R.sup.3 and R.sup.4
are independently selected from C.sub.1-10alkyl, C.sub.6-10aryl,
C.sub.3-10cycloalkyl, C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG, except when
represents .dbd.O, then R.sup.4 is not present; and one or more
available hydrogens in R.sup.3 and R.sup.4 is/are optionally
replaced with F and/or one or more of available atoms in R.sup.3
and R.sup.4 is/are optionally replaced with an isotopic label. The
N-17 secondary amine may then be selectively alkylated with any
number of alkylating reagents to provide a variety of substituents
at this position. The process is particularly useful for exploring
the structure activity relationship of different groups at this
location. In an embodiment, the N-17 secondary amine of the
compound of Formula X is selectively alkylated with a
cyclopropylmethyl, cyclobutylmethyl or allyl group.
[0012] In another embodiment, compounds of Formula VI(a), VI(b) or
VI(c) wherein X is "--C(O)R.sup.2" may be reduced, to provide the
corresponding compound of Formula XI(a), XI(b) or XI(c),
respectively:
##STR00009##
wherein R.sup.2'' is selected from C.sub.3-10cycloalkyl,
C.sub.3-10heterocycloalkyl, C.sub.1-10alkyl, C.sub.6-10aryl and
C.sub.5-10heteroaryl, each of the latter groups being unsubstituted
or substituted with one or more substituents independently selected
from C.sub.1-4alkyl, OC.sub.1-4alkyl, halo, CN, NO.sub.2,
C.sub.6-10aryl and OC.sub.6-10aryl; R.sup.3' and R.sup.4' are
independently selected from C.sub.1-10alkyl, C.sub.6-10aryl,
C.sub.3-10cycloalkyl, C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG; and one or more
available hydrogens in R.sup.2'', R.sup.3' and R.sup.4' is/are
optionally replaced with F and/or one or more of available atoms in
R.sup.2'', R.sup.3' and R.sup.4' is/are optionally replaced with an
isotopic label, wherein when PG is a protecting group that is
removed by the reducing agent, R.sup.3' and R.sup.4' are H and the
compound of Formula XI(c) converts to the ketone form.
[0013] The present application also includes compounds of Formula
IV and V, useful for the preparation of compounds of Formula I.
[0014] Other features and advantages of the present application
will become apparent from the following detailed description. It
should be understood, however, that the detailed description and
the specific examples while indicating embodiments of the
application are given by way of illustration only, since various
changes and modifications within the spirit and scope of the
application will become apparent to those skilled in the art from
this detailed description.
DETAILED DESCRIPTION OF THE APPLICATION
I. Definitions
[0015] Unless otherwise indicated, the definitions and embodiments
described in this and other sections are intended to be applicable
to all embodiments and aspects of the application herein described
for which they are suitable as would be understood by a person
skilled in the art.
[0016] As used in this application, the singular forms "a", "an"
and "the" include plural references unless the content clearly
dictates otherwise. For example, an embodiment including "a
reducing agent" should be understood to present certain aspects
with one reducing agent, or two or more additional compounds.
[0017] In embodiments comprising an "additional" or "second"
component, such as an additional or second reducing agent, the
second component as used herein is chemically different from the
other components or first component. A "third" component is
different from the other, first, and second components, and further
enumerated or "additional" components are similarly different.
[0018] The term "suitable" as used herein means that the selection
of the particular compound or conditions would depend on the
specific synthetic manipulation to be performed, and the identity
of the molecule(s) to be transformed, but the selection would be
well within the skill of a person trained in the art. All
process/method steps described herein are to be conducted under
conditions sufficient to provide the product shown. A person
skilled in the art would understand that all reaction conditions,
including, for example, reaction solvent, reaction time, reaction
temperature, reaction pressure, reactant ratio and whether or not
the reaction should be performed under an anhydrous or inert
atmosphere, can be varied to optimize the yield of the desired
product and it is within their skill to do so.
[0019] In embodiments of the application, the compounds described
herein have at least one asymmetric centre. Where compounds possess
more than one asymmetric centre, they may exist as diastereomers.
It is to be understood that all such isomers and mixtures thereof
in any proportion are encompassed within the scope of the present
application. It is to be further understood that while the
stereochemistry of the compounds may be as shown in any given
compound listed herein, such compounds may also contain certain
amounts (e.g. less than 20%, suitably less than 10%, more suitably
less than 5%) of compounds of the application having alternate
stereochemistry.
[0020] In understanding the scope of the present disclosure, the
term "comprising" and its derivatives, as used herein, are intended
to be open ended terms that specify the presence of the stated
features, elements, components, groups, integers, and/or steps, but
do not exclude the presence of other unstated features, elements,
components, groups, integers and/or steps. The foregoing also
applies to words having similar meanings such as the terms,
"including", "having" and their derivatives. The term "consisting"
and its derivatives, as used herein, are intended to be closed
terms that specify the presence of the stated features, elements,
components, groups, integers, and/or steps, but exclude the
presence of other unstated features, elements, components, groups,
integers and/or steps. The term "consisting essentially of", as
used herein, is intended to specify the presence of the stated
features, elements, components, groups, integers, and/or steps as
well as those that do not materially affect the basic and novel
characteristic(s) of features, elements, components, groups,
integers, and/or steps.
[0021] Terms of degree such as "substantially", "about" and
"approximately" as used herein mean a reasonable amount of
deviation of the modified term such that the end result is not
significantly changed. These terms of degree should be construed as
including a deviation of at least .+-.5% of the modified term if
this deviation would not negate the meaning of the word it
modifies.
[0022] The term "alkyl" as used herein, whether it is used alone or
as part of another group, means straight or branched chain,
saturated alkyl groups. The term C.sub.1-6alkyl means an alkyl
group having 1, 2, 3, 4, 5, or 6 carbon atoms. It is an embodiment
of the application that, in the alkyl groups, one or more,
including all, of the hydrogen atoms are optionally replaced with F
or .sup.2H and thus include, for example trifluoromethyl,
pentafluoroethyl and the like.
[0023] The term "alkylene" as used herein, whether alone or as part
of another group, means an alkyl group that is bivalent; i.e. that
is substituted on two ends with another group. The term
C.sub.1-10alkylene means an alkylene group having 1, 2, 3, 4, 5, 6,
7, 8, 9 or 10 carbon atoms. It is an embodiment of the application
that, in the alkylene groups, one or more, including all, of the
hydrogen atoms are optionally replaced with F or .sup.2H.
[0024] The term "alkenyl" as used herein, whether it is used alone
or as part of another group, means straight or branched chain,
unsaturated alkenyl groups. The term C.sub.2-6alkenyl means an
alkenyl group having 2, 3, 4, 5, or 6 carbon atoms and at least one
double bond. It is an embodiment of the application that, in the
alkenyl groups, one or more, including all, of the hydrogen atoms
are optionally replaced with F or .sup.2H and thus include, for
example trifluoroethenyl, pentafluoropropenyl and the like.
[0025] The term "cycloalkyl" as used herein, whether it is used
alone or as part of another group, means cyclic, saturated alkyl
groups. The term C.sub.3-10cycloalkyl means a cycloalkyl group
having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. It is an embodiment
of the application that, in the cycloalkyl groups, one or more,
including all, of the hydrogen atoms are optionally replaced with F
or .sup.2H.
[0026] The term "cycloalkenyl" as used herein, whether it is used
alone or as part of another group, means cyclic, unsaturated alkyl
groups. The term C.sub.3-10cycloalkenyl means a cycloalkenyl group
having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and at least one
double bond. It is an embodiment of the application that, in the
cycloalkenyl groups, one or more, including all, of the hydrogen
atoms are optionally replaced with F or .sup.2H.
[0027] The term "heterocycloalkyl" as used herein, whether it is
used alone or as part of another group, means cyclic, saturated
alkyl groups containing at least one heteroatom, such as N, O,
and/or S. The term C.sub.3-10heterocycloalkyl means a
heterocycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon
atoms, in which at least one of the carbon atoms has been replaced
with a heteroatom, such as N, O and/or S. It is an embodiment of
the application that, in the heterocycloalkyl groups, one or more,
including all, of the hydrogen atoms are optionally replaced with F
or .sup.2H.
[0028] The term "aryl" as used herein refers to cyclic groups that
contain at least one aromatic ring. In an embodiment of the
application, the aryl group contains 6, 9 or 10 atoms, such as
phenyl, naphthyl or indanyl. It is an embodiment of the application
that, in the aryl groups, one or more, including all, of the
hydrogen atoms are optionally replaced with F or .sup.2H and thus
include, for example pentafluorophenyl and the like.
[0029] The term "heteroaryl" as used herein refers to cyclic groups
that contain at least one aromatic ring and at least one
heteroatom, such as N, O and/or S. The term C.sub.5-10heteroaryl
means an aryl group having 5, 6, 7, 8, 9 or 10 atoms, in which at
least one atom is a heteroatom, such as N, O and/or S. It is an
embodiment of the application that, in the heteroaryl groups, one
or more, including all, of the hydrogen atoms are optionally
replaced with F or .sup.2H and thus include, for example
tetrafluoropyridyl and the like.
[0030] The term "reducing agent" as used herein means any compound
or combination of compounds that reduces a desired functional
group. A reducing agent results in the overall addition of
electrons, or in the case of organic chemistry, hydrogen atoms to
the functional group.
[0031] The term "oxidant" as used herein refers to a reagent that
provides an oxygen species for participation in the metal catalyzed
reactions of the present application. In an embodiment, the oxygen
source is O.sub.2 gas, air or an inorganic or organic peroxide
(i.e. a compound comprising an "O--O" functionality).
[0032] The term "inert solvent" as used herein means a solvent that
does not interfere with or otherwise inhibit a reaction.
Accordingly, the identity of the inert solvent will vary depending
on the reaction being performed. The selection of inert solvent is
within the skill of a person in the art. Examples of inert solvents
include, but are not limited to, benzene, toluene, tetrahydrofuran,
ethyl ether, ethyl acetate, dimethyl formamide (DMF), acetonitrile,
C.sub.1-6alkylOH (e.g. methanol, ethanol, n-propanol, 2-propanol,
n-butanol, butan-2-ol and 2-methyl-1-propanol), diethylcarbonate,
hexane and dimethylslfoxide (DMSO). Further examples, can include
aqueous solutions, such as water and dilute acids and bases, and
ionic liquids, provided that such solvents do not interfere with
the reaction.
[0033] The term "solvent" includes both a single solvent and a
mixture comprising two or more solvents.
[0034] The term "available", as in "available hydrogen atoms" or
"available atoms" refers to atoms that would be known to a person
skilled in the art to be capable of replacement by either a
fluorine atom (in the case of hydrogen atoms) or isotopic labels
(in the case of all atoms) using methods known in the art.
[0035] The term "halo" as used herein refers to a halogen atom and
includes F, Cl, Br and I.
[0036] t-Boc as used herein refers to the group
t-butyloxycarbonyl.
[0037] Ac as used herein refers to the group acetyl.
[0038] Ts (tosyl) as used herein refers to the group
p-toluenesulfonyl
[0039] Ms as used herein refers to the group methanesulfonyl
[0040] TBDMS as used herein refers to the group
t-butyldimethylsilyl.
[0041] TBDPS as used herein refers to the group
t-butyldiphenylsilyl.
[0042] TMS as used herein refers to the group trimethylsilyl.
[0043] Tf as used herein refers to the group
trifluoromethanesulfonyl.
[0044] Ns as used herein refers to the group naphthalene
sulphonyl.
[0045] Bn as used herein refers to the group benzyl.
[0046] Fmoc as used herein refers to the group
fluorenylmethoxycarbonyl.
[0047] The term "leaving group" or "LO" as used herein refers to a
group that is readily displaceable by a nucleophile, for example,
under nucleophilic substitution reaction conditions. Examples of
suitable leaving groups include, but are not limited to, halo, Ms,
Ts, Ns, Tf, C.sub.1-6acyl, and the like.
[0048] The terms "protective group" or "protecting group" or "PG"
or the like as used herein refer to a chemical moiety which
protects or masks a reactive portion of a molecule to prevent side
reactions in those reactive portions of the molecule, while
manipulating or reacting a different portion of the molecule. After
the manipulation or reaction is complete, the protecting group is
removed under conditions that do not degrade or decompose the
remaining portions of the molecule. The selection of a suitable
protecting group can be made by a person skilled in the art. Many
conventional protecting groups are known in the art, for example as
described in "Protective Groups in Organic Chemistry" McOmie, J. F.
W. Ed., Plenum Press, 1973, in Greene, T. W. and Wuts, P. G. M.,
"Protective Groups in Organic Synthesis", John Wiley & Sons,
3.sup.rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd
Edition, 2003, Georg Thieme Verlag (The Americas). Examples of
suitable protecting groups include, but are not limited to t-Boc,
Ac, Ts, Ms, silyl ethers such as TMS, TBDMS, TBDPS, Tf, Ns, Bn,
Fmoc, dimethoxytrityl, methoxyethoxymethyl ether, methoxymethyl
ether, pivaloyl, p-methyoxybenzyl ether, tetrahydropyranyl, trityl,
ethoxyethyl ethers, carbobenzyloxy, benzoyl and the like.
[0049] The expression "proceed to a sufficient extent" as used
herein with reference to the reactions or process steps disclosed
herein means that the reactions or process steps proceed to an
extent that conversion of the starting material or substrate to
product is maximized. Conversion may be maximized when greater than
about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,
80, 85, 90, 95 or 100% of the starting material or substrate is
converted to product.
II. Methods of the Application
[0050] The present application includes a process for the
preparation of a compound of Formula I:
##STR00010##
comprising: (a) reacting a compound of Formula II with a compound
of Formula IIIa or IIIb under conditions to provide a compound of
Formula IV:
##STR00011##
(b) reacting the compound of Formula IV with a metal catalyst in
air and/or in the presence of an oxidant under conditions to
provide a compound of Formula V:
##STR00012##
and (c) treating the compound of Formula V with a reducing agent
under conditions to provide the compound of Formula I, wherein each
R.sup.1 is selected from C.sub.3-10cycloalkyl, C.sub.1-10alkyl and
C.sub.6-10aryl, and each LG is a leaving group; wherein in the
compounds of the Formulae I, III, IV and V, one or more available
hydrogens in R.sup.1 is/are optionally replaced with F and/or one
or more of available atoms in R.sup.1 is/are optionally replaced
with an isotopic label.
[0051] In an embodiment of the application, R.sup.1 is selected
from C.sub.3-6cycloalkyl, C.sub.1-6alkyl and phenyl. In another
embodiment, R.sup.1 is selected from cyclopropyl, cyclobutyl,
cyclopentyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl and phenyl. In another embodiment, R.sup.1 is selected from
cyclopropyl and cyclobutyl, and the compound of Formula I is
naltrexone or nalbuphone, respectively.
[0052] In an embodiment of the application, LG is any suitable
leaving group. In a further embodiment, LG also electrophilically
activates the adjacent carbonyl group for reaction with a
nucleophile. In a further embodiment, LG is CI, Br, CN, CCl.sub.3,
imidazole, pentafluorophenyl, acyl, OC(O)R.sup.1, Ts, Ns, Ms, or
any activating group for a carboxylic acid, for example activating
groups used in peptide synthesis. In a specific embodiment, LG is
halo or OC(O)R.sup.1.
[0053] In an embodiment of the application, the conditions to
provide a compound of Formula IV comprise combining the compound of
Formula II with the compound of Formula IIIa or IIIb in the
presence of a non-nucleophilic base in an inert solvent and at
temperatures for the reaction of the compound of Formula II with
the compound of Formula IIIa or IIIb to provide the compound of
Formula IV. Examples of non-limiting reaction temperatures are
about 0.degree. C. to about 400.degree. C., about 30.degree. C. to
about 200.degree. C., or about 50.degree. C. to about 110.degree.
C. Examples of non-limiting reaction times are about 0.5 hours to
about 48 hours, or about 1 hour to about 24 hours. Examples of
suitable bases include, but are not limited to, organic amines,
such as triethylamine, pyridine, and 1,4-diazabicyclo[2.2.2]octane
(DABCO) and inorganic bases, such as hydroxides, carbonates, and
hydrogen carbonate under phase transfer conditions (i.e. the
Schotten-Baumann reaction).
[0054] The conversion of the compound of the compound of Formula IV
to the compound of Formula V involves a metal catalyzed
demethylation of the 17 position nitrogen, followed by an
intramolecular migration of the acyl group from the oxygen at C-14
to the 17 position nitrogen. Significantly, this transformation
occurs in the absence of the addition of acylating reagents, such
as R.sup.1C(O)--O--C(O)--R.sup.1. Accordingly, in an embodiment,
the compound of Formula IV is reacted with reagents consisting
essentially of, or consisting of, a metal catalyst and an oxygen
source.
[0055] The metal catalyst is any suitable metal catalyst. In an
embodiment, the catalyst is a transition metal catalyst. Examples
of complexes/compounds which can be used as the catalyst include,
but are not limited to, catalysts comprising palladium, platinum
(e.g. PtCl.sub.2 and K.sub.2PtCl.sub.4), ruthenium (e.g. Ru/C,
RuCl.sub.3xH.sub.2O, RuCl.sub.2(PPh.sub.3).sub.3, RuO.sub.2, and
tetrapropylammonium perruthenates), iron (e.g. FeCl.sub.2,
FeSO.sub.4, and iron carbonyls like Fe.sub.2(CO).sub.9), tungsten
(e.g. Na.sub.2WO.sub.4), vanadium (e.g. VO(acac).sub.2), iridium,
copper, gold, and silver complexes. In an embodiment, the catalyst
is a Pd(0) or Pd(II) catalyst, for example, but not limited to
Pd(OAc).sub.2, Pd(acac).sub.2, Pd black or palladium-perovskites,
or Pd(0) or Pd(II) catalysts on any type of solid support (e.g.
charcoal, sulfates, carbonates, alumina) or in encapsulated
form.
[0056] In another embodiment, the catalyst is used in an amount of
about 0.1 mol % to about 20 mol %, about 1 mol % to about 15 mol %
or about 5 mol % to about 10 mol %.
[0057] The conversion of the compound of Formula IV to the compound
of Formula V is suitably carried out in the presence of an oxidant,
either through the use of added O.sub.2 gas or oxidant, or by
simply carrying out the reaction in an air atmosphere. Examples of
suitable oxidants, include, but are not limited to, organic and
inorganic peroxides, such as t-butylhydroperoxide, cu men
hydroperoxide, dibutylperoxide, laurylperoxide, hydrogenperoxide,
perborates and K.sub.2S.sub.2O.sub.8.
[0058] The conversion of the compound of Formula IV to the compound
of Formula V is also suitably carried out in aqueous solutions or
in an inert solvent or a mixture of solvents, such as, but not
limited to, dioxane, toluene or benzene, DMF, C.sub.1-6alkylOH,
acetonitrile, diethylcarbonate, ionic liquids, water, dilute
aqueous acid and dilute aqueous base, and at temperatures and time
sufficient for the conversion to proceed to a sufficient extent. In
a further embodiment, the solvent or mixture of solvents consists
of, consists essentially of or comprises a C.sub.1-4alcohol, in
particular methanol, ethanol, n-propanol, 2-propanol, n-butanol,
butan-2-ol or 2-methyl-1-propanol. Non-limiting examples of
suitable temperatures are from about 10.degree. C. to about
400.degree. C., about 50.degree. C. to about 200.degree. C. or
about 75.degree. C. to about 125.degree. C. Examples of
non-limiting reaction times are about 0.5 hours to about 64 hours,
about 1 hour to about 48 hours, or about 5 hours to about 30 hours.
In a further embodiment of the application, the conversion of the
compound of Formula IV to the compound of Formula V is carried out
in the presence of a co-catalyst. Examples of co-catalysts include,
but are not limited to copper salts such as copper acetate and
copper chloride, and all oxophilic metals and their complexes, such
as cerium salts.
[0059] The reduction of the compound of Formula V to the compounds
of Formula I is carried out using any reducing agent suitable for
reducing the 17 position carbonyl to a CH.sub.2 group and for
removing the acyl group on the 3 and 6 position hydroxyl groups,
with concomitant rearrangement of the enol to the keto form.
Examples of such reducing agents include, but are not limited to,
metal hydride reducing agents including lithium aluminum hydride
and sodium bis(2-methoxyethoxy)aluminum hydride, hydrosilylation
reagents and hydroboration reagents. In an embodiment, the
reduction is carried out using sodium bis(2-methoxyethoxy)aluminum
hydride in an inert solvent or mixture of solvents at a temperature
and for a time sufficient for the reduction to proceed to a
sufficient extent. As a representative, non-limiting example, the
temperature for the reduction of the compound of Formula V to the
compound of Formula I is about 0.degree. C. to about 400.degree.
C., about 20.degree. C. to about 200.degree. C., or about
50.degree. C. to about 100.degree. C. and examples of non-limiting
reaction times are about 1 minute to about 24 hours, about 10
minutes to about 12 hours, or about 15 minutes to about 1 hour.
[0060] In an embodiment of the application, the compound of Formula
II is oxymorphone which is readily available, for example, from
oripavine or thebaine on an industrial scale.sup.viii. Compounds of
Formula IIIa and IIIb are commercially available or may be prepared
using methods known in the art. For example, carboxylic acid
anhydrides may be prepared by reaction of the carboxylic acid,
corresponding acyl chloride, and a base, such as triethylamine, in
a nonpolar solvent system. The precipitated base hydrochloride can
be filtered off and, after concentration of the filtrate, the
product distilled under reduced pressure or purified using other
known methods. This procedure is suitable for multigram
preparation.
[0061] As a representative example of the process of the present
application, an expedient route to naltrexone from oxymorphone was
carried out that involved intramolecular acyl transfer during
demethylation. Thus oxymorphone was peracylated either with
cyclopropyl carboxylic acid anhydride, or with the corresponding
acyl chloride, which is much less expensive, and converted to the
fully acylated product. Exposure of this material to anhydride free
conditions of N-demethylation provided an excellent yield of the
N-acyl amide, isolated as a mixture of N-acyl diastereoisomers,
whose reduction with Vitride.TM. (sodium
bis(2-methoxyethoxy)aluminum hydride) furnished in 93% yield
naltrexone. The N-demethylation/acylation protocol was subjected to
a more detailed investigation. The reactions were conducted in the
absence of additional cylopropylcarboxylic acid anhydride taking
advantage of the intramolecular acyl transfer from the neighboring
C-14 ester. A 92% yield of the N-acyl amide was obtained when Pd(C)
was used in dioxane in the presence of air at 100.degree. C. In
DMF-water mixture (5:1) and Pd(OAC).sub.2 as a catalyst the yield
of the N-acyl amide was 95% after 23 hours at 100.degree. C.
Somewhat lower yield (85%, with 7-8% recovery of the starting
material) was obtained when Pd(C) was employed in DMF-water
mixture. The full reduction of the N-acyl amide to naltrexone with
Vitride.TM. deserves a comment. First of all, Vitride.TM. is a very
convenient and inexpensive reducing agent, whose use at industrial
scales is optimal compared to other, less safe reducing agents such
as lithium aluminum hydride. Second, the reduction is extremely
fast probably in part because of the anchimeric assistance of C-14
hydroxyl and reagent delivery through chelation.
[0062] The three-step transformation of oxymorphone to naltrexone
proceeded with an overall yield of .about.75% and can likely be
further optimized, possibly even reduced to a one-pot procedure
without isolation or purification.
[0063] The process of the present application may be extended to
other C-14 hydroxy morphine analogs and the intramolecular transfer
of other functional groups. Therefore, the present application also
includes a process for the preparation of a compound of Formula
VI:
##STR00013##
wherein X is selected from C(O)R.sup.2, S(O)R.sup.2,
SO.sub.2R.sup.2, P(O)R.sup.2R.sup.2', P(O)(OR.sup.2)R.sup.2' and
P(O)(OR.sup.2)(OR.sup.2'); R.sup.2 and R.sup.2' are independently
selected from C.sub.3-10cycloalkyl, C.sub.3-10heterocycloalkyl,
C.sub.3-10cycloalkenyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.6-10aryl and C.sub.5-10heteroaryl, each of the latter groups
being unsubstituted or substituted with one or more substituents
independently selected from C.sub.1-4alkyl, OC.sub.1-4alkyl, halo,
CN, NO.sub.2, C.sub.6-10aryl and OC.sub.6-10aryl; represents a
single or double bond, provided that two double bonds are not
adjacent to each other; and R.sup.3 and R.sup.4 are independently
selected from C.sub.1-10alkyl, C.sub.6-10aryl,
C.sub.3-10cycloalkyl, C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG, except when
represents .dbd.O, then R.sup.4 is not present; the process
comprising: (a) reacting a compound of Formula VII with a compound
of Formula VIII(a) or VIII(b) under conditions to provide a
compound of Formula IX:
##STR00014##
wherein LG.sup.1 is a leaving group; X is selected from
C(O)R.sup.2, S(O)R.sup.2, SO.sub.2R.sup.2, P(O)R.sup.2R.sup.2',
P(O)(OR.sup.2)R.sup.2' and P(O)(OR.sup.2)(OR.sup.2'); R.sup.2 and
R.sup.2' are independently selected from C.sub.3-10cycloalkyl,
C.sub.3-10heterocycloalkyl, C.sub.3-10cycloalkenyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.6-10aryl and
C.sub.5-10heteroaryl, each of the latter groups being unsubstituted
or substituted with one or more substituents independently selected
from C.sub.1-4alkyl, OC.sub.1-4alkyl, halo, CN, NO.sub.2,
C.sub.6-10aryl and OC.sub.6-10aryl; represents a single or double
bond, provided that two double bonds are not adjacent to each
other; and R.sup.3 and R.sup.4 are independently selected from
C.sub.1-10alkyl, C.sub.6-10aryl, C.sub.3-10cycloalkyl,
C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG, except when
represents .dbd.O, then R.sup.4 is not present; and (b) reacting
the compound of Formula IX with a metal catalyst in the presence of
an oxidant under conditions to provide the compound of Formula VI,
wherein in the compounds of Formulae VI, VII, VIII and IX, one or
more available hydrogens in R.sup.2, R.sup.2', R.sup.3 and R.sup.4
is/are optionally replaced with F and/or one or more of available
atoms in R.sup.2, R.sup.2', R.sup.3 and R.sup.4 is/are optionally
replaced with an isotopic label.
[0064] In an embodiment of the application, R.sup.2 and R.sup.2'
are independently selected from C.sub.3-6cycloalkyl, C.sub.1-6alkyl
and phenyl. In another embodiment, R.sup.2 and R.sup.2' are
independently selected from cyclopropyl, cyclobutyl, cyclopentyl,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and
phenyl. In another embodiment, R.sup.2 and R.sup.2' are
independently selected from cyclopropyl and cyclobutyl.
[0065] In an embodiment of the application, LG.sup.1 is any
suitable leaving group. In a further embodiment, LG.sup.1 also
electrophilically activates the adjacent group for reaction with a
nucleophile. In a further embodiment, LG.sup.1 is CI, Br, CN,
CCl.sub.3, imidazole, pentafluorophenyl, acyl, O--X, Ts, Ns, Ms, or
any activating group, for example activating groups used in peptide
synthesis. In a specific embodiment, LG is Cl or O--X.
[0066] It is an embodiment that X is C(O)R.sup.2.
[0067] In an embodiment, R.sup.3 and R.sup.4 are independently
selected from C.sub.1-6alkyl, phenyl, napthyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkyleneC.sub.6-10aryl,
C.sub.1-6alkyleneC.sub.3-6cycloalkyl and PG, except when represents
.dbd.O, then R.sup.4 is not present. In an embodiment, PG is a
group that is compatible with the reaction conditions so that it is
not removed or altered during the preparation of the compounds of
Formula VI, but can be removed from the compounds of Formula VI
upon completion of the process. Examples of suitable PG, include,
but are not limited to acyl, alkoxycarbonyl, Bn, methoxymethyl
(MOM), alkyl carbonates and arylcarbonates.
[0068] In an embodiment, the compound of Formula VI is selected
from a compound of Formula VI(a), VI(b) and VI(c):
##STR00015##
wherein X is selected from C(O)R.sup.2, S(O)R.sup.2,
SO.sub.2R.sup.2, P(O)R.sup.2R.sup.2', P(O)(OR.sup.2)R.sup.2' and
P(O)(OR.sup.2)(OR.sup.2'); R.sup.2 and R.sup.2' are independently
selected from C.sub.3-10cycloalkyl, C.sub.3-10heterocycloalkyl,
C.sub.3-10cycloalkenyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.6-10aryl and C.sub.5-10heteroaryl, each of the latter groups
being unsubstituted or substituted with one or more substituents
independently selected from C.sub.1-4alkyl, OC.sub.1-4alkyl, halo,
CN, NO.sub.2, C.sub.6-10aryl and OC.sub.6-10aryl; represents a
single or double bond; R.sup.3 and R.sup.4 are independently
selected from C.sub.1-10alkyl, C.sub.6-10aryl,
C.sub.3-10cycloalkyl, C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG, and one or more
available hydrogens in R.sup.2, R.sup.2', R.sup.3 and R.sup.4
is/are optionally replaced with F and/or one or more of available
atoms in R.sup.2, R.sup.2', R.sup.3 and R.sup.4 is/are optionally
replaced with an isotopic label.
[0069] In another embodiment, the compound of Formula VI is a
compound of Formula VI(a) or VI(b) wherein represents a single
bond.
[0070] In an embodiment of the application, the conditions to
provide a compound of Formula IX comprise combining the compound of
Formula VII with the compound of Formula VIII(a) or VIII(b) in the
presence of a non-nucleophilic base in an inert solvent and at
temperatures for the reaction of the compound of Formula VII with
the compound of Formula VIII(a) or VIII(b) to provide the compound
of Formula IX. Examples of non-limiting reaction temperatures are
about 0.degree. C. to about 400.degree. C., about 30.degree. C. to
about 200.degree. C., or about 50.degree. C. to about 110.degree.
C. Examples of non-limiting reaction times are about 0.5 hours to
about 48 hours, or about 1 hour to about 24 hours. Examples of
suitable bases include, but are not limited to, organic amines,
such as triethylamine, pyridine, and 1,4-diazabicyclo[2.2.2]octane
(DABCO) and inorganic bases, such as hydroxides, carbonates, and
hydrogen carbonate under phase transfer conditions (i.e. the
Schotten-Baumann reaction).
[0071] The conversion of the compound of the compound of Formula IX
to the compound of Formula VI involves a metal-catalyzed
demethylation of the 17 position nitrogen, followed by an
intramolecular migration of the "--X" group from the oxygen at C-14
to the 17 position nitrogen. Significantly, this transformation
occurs in the absence of the addition of reagents, such as
R.sup.2C(O)--O--C(O)--R.sup.2, R.sup.2--S(O)--O--S(O)--R.sup.2,
R.sup.2--SO.sub.2--O--SO.sub.2--R.sup.2, Cl--P(O)R.sup.2R.sup.2',
Cl--P(O)(OR.sup.2)R.sup.2' and Cl--P(O) (OR.sup.2)(OR.sup.2).
Accordingly, in an embodiment, the compound of Formula IX is
reacted with reagents consisting essentially of, or consisting of,
a metal catalyst and an oxidant.
[0072] The metal catalyst is any suitable metal catalyst. In an
embodiment, the catalyst is a transition metal catalyst. Examples
of complexes/compounds which can be used as the catalyst include,
but are not limited to, catalysts comprising palladium, platinum
(e.g. PtCl.sub.2 and K.sub.2PtCl.sub.4), ruthenium (e.g. Ru/C,
RuCl.sub.3xH.sub.2O, RuCl.sub.2(PPh.sub.3).sub.3, RuO.sub.2, and
tetrapropylammonium perruthenates), iron (e.g. FeCl.sub.2,
FeSO.sub.4, and iron carbonyls like Fe.sub.2(CO).sub.9), tungsten
(e.g. Na.sub.2WO.sub.4), vanadium (e.g. VO(acac).sub.2), iridium,
copper, gold, and silver complexes. In an embodiment, the catalyst
is a Pd(0) or Pd(II) catalyst, for example, but not limited to
Pd(OAc).sub.2, Pd(acac).sub.2, Pd black or palladium-perovskites,
or Pd(0) or Pd(II) catalysts on any type of solid support (e.g.
charcoal, sulfates, carbonates, alumina) or in encapsulated
form.
[0073] In another embodiment, the catalyst is used in an amount of
about 0.1 mol % to about 20 mol %, about 1 mol % to about 15 mol %
or about 5 mol % to about 10 mol %.
[0074] The conversion of the compound of Formula IX to the compound
of Formula VI is suitably carried out in the presence of an
oxidant, either through the use of added O.sub.2 gas or oxidant, or
by simply carrying out the reaction in an air atmosphere. Examples
of suitable oxidants, include, but are not limited to organic and
inorganic peroxides, such as t-butylhydroperoxide, cu men
hydroperoxide, dibutylperoxide, laurylperoxide, hydrogenperoxide,
perborates and K.sub.2S.sub.2O.sub.8.
[0075] The conversion of the compound of Formula IX to the compound
of Formula VI is also suitably carried out in aqueous solutions or
in an inert solvent or a mixture of solvents, such as, but not
limited to, dioxane, toluene or benzene, DMF, C.sub.1-6alkylOH,
acetonitrile, diethylcarbonate, ionic liquids, water, dilute
aqueous acid and dilute aqueous base, and at temperatures and time
sufficient for the conversion to proceed to a sufficient extent. In
a further embodiment, the solvent or mixture of solvents consists
of, consists essentially of or comprises a C.sub.1-4alcohol, in
particular methanol, ethanol, n-propanol, 2-propanol, n-butanol,
butan-2-ol or 2-methyl-1-propanol. Non-limiting examples of
suitable temperatures are from about 10.degree. C. to about
400.degree. C., about 50.degree. C. to about 200.degree. C. or
about 75.degree. C. to about 125.degree. C. Examples of
non-limiting reaction times are about 0.5 hours to about 64 hours,
about 1 hour to about 48 hours, or about 5 hours to about 30 hours.
In a further embodiment of the application, the conversion of the
compound of Formula IX to the compound of Formula VI is carried out
in the presence of a co-catalyst. Examples of co-catalysts include,
but are not limited to copper salts such as copper acetate and
copper chloride, and all oxophilic metals and their complexes, such
as cerium salts.
[0076] The compounds of Formula VI are useful intermediates in the
preparation of morphine alkaloids. For example, in one embodiment,
the "--X" group may selectively be removed, via acid or base
hydrolysis, from N-17, to provide the corresponding secondary amine
of Formula X:
##STR00016##
wherein represents a single or double bond, provided that two
double bonds are not adjacent to each other; R.sup.3 and R.sup.4
are independently selected from C.sub.1-10alkyl, C.sub.6-10aryl,
C.sub.3-10cycloalkyl, C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG, except when
represents .dbd.O, then R.sup.4 is not present; and one or more
available hydrogens in R.sup.3 and R.sup.4 is/are optionally
replaced with F and/or one or more of available atoms in R.sup.3
and R.sup.4 is/are optionally replaced with an isotopic label. The
N-17 secondary amine may then be selectively alkylated with any
number of alkylating reagents to provide a variety of substituents
at this position. The process is particularly useful for exploring
the structure activity relationship of different groups at this
location. In an embodiment, the N-17 secondary amine of the
compound of Formula X is selectively alkylated with a
cyclopropylmethyl, cyclobutylmethyl or allyl group.
[0077] In another embodiment, compounds of Formula VI(a), VI(b) or
VI(c) wherein X is "--C(O)R.sup.2" may be reduced, to provide the
corresponding compound of Formula XI(a), XI(b) or XI(c),
respectively:
##STR00017##
wherein R.sup.2'' is selected from C.sub.3-10cycloalkyl,
C.sub.3-10heterocycloalkyl, C.sub.1-10alkyl, C.sub.6-10aryl and
C.sub.5-10heteroaryl, each of the latter groups being unsubstituted
or substituted with one or more substituents independently selected
from C.sub.1-4alkyl, OC.sub.1-4alkyl, halo, CN, NO.sub.2,
C.sub.6-10aryl and OC.sub.6-10aryl; R.sup.3' and R.sup.4' are
independently selected from C.sub.1-10alkyl, C.sub.6-10aryl,
C.sub.3-10cycloalkyl, C.sub.1-10alkyleneC.sub.6-10aryl,
C.sub.1-10alkyleneC.sub.3-10cycloalkyl and PG; and one or more
available hydrogens in R.sup.2'', R.sup.3' and R.sup.4' is/are
optionally replaced with F and/or one or more of available atoms in
R.sup.2'', R.sup.3' and R.sup.4' is/are optionally replaced with an
isotopic label, wherein when PG is a protecting group that is
removed by the reducing agent, R.sup.3' and R.sup.4' are H and the
compound of Formula XI(c) converts to the ketone form.
[0078] In another embodiment of the present application, when one
or both of R.sup.3' and R.sup.4' are PG, the processes of the
present application further include removal of the protecting
groups to provide the free "--OH" compounds.
[0079] The processes of the present application may be performed
using continuous or batch processes. For commercial scale
preparations continuous processes are suitable. Methods of
performing chemical processes in continuous or batch modes are
known in the art. When continuous processes are used, the reaction
temperature and/or pressure may be higher than those used in batch
processes.
III. Compounds of the Application
[0080] The present application also includes compounds of Formula
IV and V, useful for the preparation of compounds of Formula I.
[0081] Accordingly, the present application includes a compound of
Formula IV or V:
##STR00018##
wherein R.sup.1 is, independently, selected from
C.sub.3-10cycloalkyl, C.sub.1-10alkyl and C.sub.6-10aryl.
[0082] In an embodiment of the application, R.sup.1 in the compound
of Formula IV or V is, independently selected from
C.sub.3-6cycloalkyl, C.sub.1-6alkyl and phenyl. In another
embodiment, R.sup.1 in the compound of Formula IV or V is,
independently selected from cyclopropyl, cyclobutyl, cyclopentyl,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and
phenyl. In another embodiment, R.sup.1 in the compound of Formula
IV or V is, independently selected from cyclopropyl and
cyclobutyl.
[0083] The following non-limiting examples are illustrative of the
present application:
EXAMPLES
Example 1
3,14-Diacetyloxymorphone
##STR00019##
[0085] A suspension of oxymorphone (3.20 g; 10.63 mmol), acetic
anhydride (8.68 g; 85.04 mmol) and toluene (30 mL) was placed into
a pre-heated oil bath at 80.degree. C. After 15 mins of stirring
all solid dissolved and the pale yellow solution was stirred at
80.degree. C. for 1 h, after which time it was allowed to stir
overnight at room temperature. The excess anhydride was removed by
azeotropic distillation with toluene and the mixture was
concentrated to a thick slurry, which was dissolved in
dichloromethane. This solution was washed with sat. NaHCO.sub.3 (10
mL) and the aqueous layer was extracted with dichloromethane.
(3.times.5 mL). Combined organic layers were washed with water,
brine, dried over Na.sub.2SO.sub.4 and concentrated.
Crystallization from EtOH (12 mL) and MeOH (3 mL) afforded 3.48 g
of product. The mother liquor was concentrated and chromatographed
(eluent EtOAc+10% MeOH). Crystallization of collected material
afforded additional 0.27 g of product for the overall yield of 91%
of the title compound.
[0086] mp 218-220.degree. C. (EtOH); R.sub.f 0.53 (ethyl
acetate+20% methanol); [.alpha.].sup.22.sub.D=-180.00 (c=1.0,
CHCl.sub.3); IR (CHCl.sub.3) v 3027, 2936, 2805, 1761, 1728, 1626,
1446, 1370, 1216, 1156 cm.sup.-1; .sup.1H NMR (600 MHz, CDCl.sub.3)
6.87 (d, J=8.1 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 4.69 (s, 1H), 4.22
(d, J=5.4 Hz, 1H), 3.25 (d, J=18.8 Hz, 1H), 2.82 (ddd, J=14.3, 5.0,
2.6 Hz, 1H), 2.63 (ddd, J=14.7, 14.7, 5.4 Hz, 1H), 2.56-2.46 (m,
3H), 2.33 (s, 3H), 2.32 (s, 3H), 2.31 (m, 1H), 2.19 (s, 3H), 2.17
(m, 1H), 1.64 (ddd, J=14.2, 14.2, 3.8 Hz, 1H), 1.55 (m, 1H);
.sup.13C NMR (150 MHz, CDCl.sub.3) .delta. 206.51, 170.22, 168.45,
147.65, 132.53, 131.30, 129.02, 123.14, 119.55, 90.23, 82.15,
57.62, 50.32, 45.42, 42.68, 35.52, 30.07, 26.78, 22.60, 22.24,
20.83; MS (+FAB) m/z (%): 43 (52), 326 (100), 343 (72), 386 (65);
HRMS calcd for C.sub.21H.sub.23NO.sub.6.sup.+ 386.1598, found
386.15627.
Example 2
3,17-diacetyl-noroxymorphone
##STR00020##
[0088] A mixture of 3,14-diacetyloxymorphone (Example 1, 1.0 g;
2.594 mmol), Pd(OAc).sub.2 (0.011 g; 0.052 mmol) and dioxane (10
mL) was stirred at 80.degree. C. under oxygen atmosphere for two
days. When the TLC analysis showed that the starting material
disappeared, the mixture was concentrated to a thick oil and loaded
onto a chromatography column. Chromatography (eluent EtOAc+10%
MeOH) afforded 0.89 g (92%) of white solid as a 1:4 mixture of the
title compound; mp >235.degree. C. (EtOH); R.sub.f 0.32 (ethyl
acetate+10% methanol; IR (CHCl.sub.3) v 3364, 3025, 3009, 2957,
2933, 1762, 1728, 1622, 1443, 1370, 1156, 1036 cm.sup.-1;
[0089] Major Isomer:
[0090] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.90 (d, J=8.2 Hz,
1H), 6.75 (d, J=8.2 Hz, 1H), 5.10 (d, J=5.9 Hz, 1H), 4.73 (s, 1H),
4.35 (s, 1H), 3.66 (dd, J=14.0, 4.8 Hz, 1H), 3.15-3.04 (m, 3H),
2.88 (d, J=18.7 Hz, 1H), 2.63 (ddd, J=12.6, 12.6, 5.2 Hz, 1H), 2.33
(s, 3H), 2.30 (m, 1H), 2.16 (s, 3H), 2.02 (m, 1H), 1.70 (ddd,
J=14.0, 14.0, 3.4 Hz, 1H), 1.58 (dd, J=12.6, 3.0 Hz, 1H); .sup.13C
NMR (150 MHz, CDCl.sub.3) .delta. 207.27, 171.15, 168.53, 147.94,
132.92, 129.52, 129.37, 123.52, 119.89, 90.19, 70.48, 53.32, 50.35,
39.98, 35.71, 31.79, 31.73, 28.84, 22.18, 20.83;
[0091] Minor Isomer:
[0092] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.90 (d, J=8.2 Hz,
1H), 6.75 (d, J=8.2 Hz, 1H), 4.73 (s, 1H), 4.48 (dd, J=14.3, 4.9
Hz, 1H), 4.35 (s, 1H), 4.11 (d, J=5.6 Hz, 1H), 3.71 (m, 1H), 3.20
(dd, J=18.6, 5.9 Hz, 1H), 3.11 (m, 1H), 3.01 (d, J=18.4 Hz, 1H),
2.55 (ddd, J=13.6, 13.6, 4.2 Hz, 1H), 2.38 (m, 1H), 2.25 (s, 3H),
1.97 (m, 1H), 1.71-1.66 (m, 2H); .sup.13C NMR (150 MHz, CDCl.sub.3)
.delta. 206.93, 170.89, 168.40, 147.94, 133.06, 129.27, 128.67,
123.71, 119.82, 90.12, 70.83, 59.68, 50.35, 39.98, 34.42, 32.42,
31.13, 28.84, 22.32, 20.82;
[0093] MS (+EI) m/z (%): 43 (63), 84 (100), 244 (1 3), 287 (4), 311
(4), 329 (34), 371 (7); HRMS calcd for C.sub.20H.sub.21NO.sub.6
371.1369, found 371.13633.
Example 3
3,6,14-Tris(cyclopropylcarboxy)oxymorphone
##STR00021##
[0095] A suspension of oxymorphone (1.56 g; 5.19 mmol),
cyclopropylcarboxylic acid anhydride (4.0 g; 25.95 mmol), and
toluene (20 mL) was stirred at 80.degree. C. for 160 min. Then
DABCO was added in one portion (1.16 g; 10.38 mmol) and the
resulting mixture was stirred at 80.degree. C. over 15 h. After
this time the conversion was incomplete and an additional amount of
anhydride (1.60 g; 10.38 mmol) was added and mixture was stirred at
80.degree. C. for 5 h. Then the reaction mixture was allowed to
cool down, concentrated in vacuo, and the excess anhydride was
removed under high vacuum. The mixture was diluted with
dichloromethane (20 mL), washed with sat. NaHCO.sub.3 (5 mL) and
the aqueous layer was extracted with dichloromethane (3.times.5
mL). Combined organic layers were washed with water, brine, dried
over Na.sub.2SO.sub.4 and concentrated. Column chromatography
(eluent EtOAc.fwdarw.EtOAc+10% MeOH) afforded 2.37 g (90%) of the
title compound as a white solid.
[0096] This reaction could also be performed using
cyclopropylcarboxylic acid chloride (less expensive) and
triethylamine in ethyl acetate as the solvent at 80.degree. C. to
obtain 92% of the titled compound.
[0097] mp 158-160.degree. C. (EtOH); R.sub.f 0.40 (ethyl
acetate:hexane/1:1); [.alpha.].sup.22.sub.D=-122.96 (c=1.0,
CHCl.sub.3); IR (CHCl.sub.3) v 3025, 2934, 2849, 1743, 1716, 1440,
1387, 1100, 1032 cm.sup.-1; .sup.1H NMR (600 MHz, CDCl.sub.3)
.delta. 6.86 (d, J=8.2 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H), 5.42 (dd,
J=6.0, 1.6 Hz, 1H), 5.08 (s, 1H), 4.22 (d, J=6.0 Hz, 1H), 3.21 (d,
J=18.8 Hz, 1H), 3.05 (dd, J=18.3, 6.2 Hz, 1H), 2.55 (dd, J=18.8,
6.2 Hz, 1H), 2.47 (dd, J=11.8, 4.7 Hz, 1H), 2.38 (ddd, J=12.3,
12.3, 5.2 Hz, 1H), 2.31 (s, 3H), 2.22 (ddd, J=12.0, 12.0, 3.4 Hz,
1H), 2.04 (d, J=18.4 Hz, 1H), 1.87 (m, 1H), 1.77-1.69 (m, 1H),
1.65-1.58 (m, 2H), 1.21 (m, 1H), 1.18 (m, 1H), 1.14-1.09 (m, 3H),
1.05 (m, 1H), 1.04-1.00 (m, 2H), 0.99-0.94 (m, 2H), 0.90-0.82 (m,
2H); .sup.13C NMR (150 MHz, CDCl.sub.3) .delta. 174.08, 173.21,
172.47, 147.37, 143.85, 133.30, 131.59, 130.69, 122.69, 118.87,
116.56, 86.88, 81.02, 57.45, 47.06, 45.07, 42.87, 30.28, 27.27,
22.96, 14.52, 12.97, 12.81, 9.367, 9.23, 9.16, 9.05, 8.55, 8.43; MS
(+EI) m/z (%): 41 (48), 56 (55), 69 (100), 86 (100), 124 (20), 167
(16), 437 (16), 505 (12); HRMS calcd for C.sub.29H.sub.31NO.sub.7
505.2101, found 505.21049.
Example 4
3,6,17-Tris(cyclopropylcarboxy)oxymorphone
##STR00022##
[0099] A mixture of 3,6,14-tris(cyclopropylcarboxy)oxymorphone (1.0
g; 1.98 mmol), Pd(OAc).sub.2 (0.009 g; 0.004 mmol), and dioxane (10
mL) was stirred at 100.degree. C. over 24 h under oxygen
atmosphere. After 5 min of stirring a thick Pd black precipitate
was observed. When the starting material disappeared (vide TLC) the
mixture was concentrated and loaded onto a column. Column
chromatography (eluent EtOAc) afforded 0.85 g (87%) of the title
compound as a mixture (1:4) of amide isomers that was easy to
crystallize; mp 130-133.degree. C. (MeOH); R.sub.f 0.46 (ethyl
acetate); IR (CHCl.sub.3) v 3573, 3419, 3013, 2919, 1747, 1618,
1448, 1386, 1149, 1032.
[0100] The N-demethylation/acylation protocol was subjected to more
detailed investigation. The reactions were conducted in the absence
of additional cylopropylcarboxylic acid anhydride taking advantage
of the intramolecular acyl transfer from the neighboring C-14
ester. A 92% yield of the title compound was obtained when Pd(C)
was used in dioxane in the presence of air at 100.degree. C. In
DMF-water mixture (5:1) and Pd(OAC).sub.2 as a catalyst the yield
of the title compound was 95% after 23 hours at 100.degree. C.
Somewhat lower yield (85%, with 7-8% recovery of the starting
material) was obtained when Pd(C) was employed in DMF-water
mixture.
[0101] Major Isomer:
[0102] 1H NMR (600 MHz, CDCl.sub.3) .delta. 6.89 (d, J=8.0 Hz, 1H),
6.68 (d, J=8.0 Hz, 1H), 5.53 (s, 1H), 5.10 (m, 1H), 5.07 (s, 1H),
4.07 (d, J=11.0 Hz, 1H), 3.30-3.13 (m, 2H), 2.89 (d, J=18.6 Hz,
1H), 2.51 (m, 1H), 2.24 (m, 1H), 2.17 (m, 1H), 1.86 (m, 1H), 1.78
(m, 1H), 1.72 (m, 1H), 1.65 (m, 1H), 1.24-1.14 (m, 2H), 1.09 (m,
2H), 1.05 (m, 2H), 1.00-0.91 (m, 4H), 0.78 (m, 2H); .sup.13C NMR
(150 MHz, CDCl.sub.3) .delta. 174.07, 173.17, 172.48, 147.69,
143.44, 133.59, 131.05, 130.05, 123.08, 119.19, 117.26, 86.72,
71.24, 53.62, 47.44, 38.73, 32.71, 32.44, 29.37, 12.95, 12.81,
11.75, 9.39, 9.27, 9.17, 9.05, 7.76, 7.41.
[0103] Minor Isomer:
[0104] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.89 (d, J=8.0 Hz,
1H), 6.68 (d, J=8.0 Hz, 1H), 5.53 (s, 1H), 5.01 (s, 1H), 4.47 (m,
1H), 3.27 (m, 1H), 3.03 (d, J=18.3 Hz, 1H), 2.65 (dd, J=12.0, 11.0
Hz, 1H), 2.38-2.12 (m, 3H), 1.90-1.63 (m, 4H), 1.24-1.14 (m, 2H),
1.09 (m, 2H), 1.05 (m, 2H), 1.00-0.91 (m, 4H), 0.78 (m, 2H);
.sup.13C NMR (150 MHz, CDCl.sub.3) .delta. 174.07, 173.35, 172.39,
147.69, 143.69, 133.69, 131.05, 129.52, 123.21, 119.19, 117.15,
86.60, 71.11, 57.52, 47.58, 34.79, 33.11, 32.14, 28.64, 12.95,
12.81, 11.75, 9.39, 9.27, 9.17, 9.05, 7.77, 7.22; MS (+EI) m/z (%):
41 (36), 69 (100), 112 (9), 226 (6), 294 (3), 354 (4), 423 (5), 491
(10); HRMS calcd for C.sub.28H.sub.29NO.sub.7 491.1944, found
491.19479.
Example 5
Naltrexone
##STR00023##
[0106] A flame-dried flask thoroughly purged with nitrogen was
charged with Vitride.TM. (0.76 g of 65% solution in toluene; 2.44
mmol). A solution of amide
3,6,17-tris(cyclopropylcarboxy)oxymorphone (0.20 g; 0.407 mmol) in
THF (2 mL) was added over 30 sec. When bubbling ceased the mixture
was placed into a pre-heated oil bath at 80.degree. C. After
refluxing for 30 min the mixture was allowed to cool down, quenched
with cold solution of Rochell's salt (2 mL), water (2 mL), and
diluted with dichloromethane (3 mL). After extraction and
separation of organic layer sat. NH.sub.4Cl (0.5 mL) was added to
the aqueous layers and product was extracted with dichloromethane.
Addition of solution of NH.sub.4Cl (0.5 mL) and extraction was
repeated three times. The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4 and concentrated.
Naltrexone, 0.13 g (93%), was obtained by column chromatography
(eluent EtOAc+20% MeOH) as a white solid.
[0107] Vitride.TM. is a very convenient and inexpensive reducing
agent, whose use at industrial scales is optimal to other, less
safe reducing agents such as lithium aluminum hydride. The
reduction is extremely fast probably in part because of the
anchimeric assistance of C-14 hydroxyl and reagent delivery through
chelation.
[0108] mp 159-161.degree. C. (MeOH), [lit. mp 174-176.degree. C.
(acetone)]'.sup.X; R.sub.f 0.42 (ethyl acetate+20% MeOH);
[.alpha.].sup.20.sub.D=-207.00 (c=1, CHCl.sub.3); IR (CHCl.sub.3) v
3568, 3359, 3010, 2931, 2834, 1723, 1620, 156, 1317, 1146, 1058,
943; .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.74 (d, J=8.1 Hz,
1H), 6.60 (d, J=8.1 Hz, 1H), 5.82 (bs, 1H, OH), 4.74 (s, 1H), 3.21
(d, J=5.9 Hz, 1H), 3.11-3.03 (m, 2H), 2.72 (dd, J=12.0, 4.8 Hz,
1H), 2.58 (dd, J=18.4, 6.0 Hz, 1H), 2.49-2.39 (m, 3H), 2.34 (ddd,
J=14.5, 3.0, 3.0 Hz, 1H), 2.18 (ddd, J=12.2, 3.8, 3.8 Hz, 1H), 1.91
(m, 1H), 1.66 (ddd, J=14.2, 14.2, 3.3 Hz, 1H), 1.59 (ddd, J=12.8,
2.7 Hz, 1H), 0.88 (m, 1H), 0.57 (m, 2H), 0.16 (m, 2H); .sup.13C NMR
(150 MHz, CDCl.sub.3) .delta. 210.02, 142.51, 138.80, 129.05,
124.25, 119.90, 117.91, 90.60, 70.32, 62.01, 59.21, 51.07, 43.60,
36.21, 31.36, 30.65, 22.62, 9.42, 4.02, 3.81; MS (+EI) m/z (%): 47
(15), 55 (41, 84 (100), 110 (12), 202 (5), 256 (12), 286 (7), 300
(15), 341 (64); HRMS calcd for C.sub.20H.sub.23NO.sub.4 341.1627,
found 341.16320.
[0109] While the present application has been described with
reference to what are presently considered to be the preferred
examples, it is to be understood that the application is not
limited to the disclosed examples. To the contrary, the application
is intended to cover various modifications and equivalent
arrangements included within the spirit and scope of the appended
claims.
[0110] All publications, patents and patent applications are herein
incorporated by reference in their entirety to the same extent as
if each individual publication, patent or patent application was
specifically and individually indicated to be incorporated by
reference in its entirety. Where a term in the present application
is found to be defined differently in a document incorporated
herein by reference, the definition provided herein is to serve as
the definition for the term.
FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE APPLICATION
[0111] .sup.i Von Braun, J. Chem. Ber. 1980, 33, 1438. [0112]
.sup.ii Cooley, J. H.; Evain, E. J. Synthesis 1989, 1; Olofson, R.
A. et al. J. Org. Chem. 1984, 49, 2081. [0113] .sup.iii Ripper, J.
A., et al. Biorg. & Med. Chem. Lett. 2001, 11, 443-445. [0114]
.sup.iv (a) Kok, G. et al. Adv. Synth. Catal. 2009, 351, 283; (b)
Dong, Z. et al. J. Org. Chem. 2007, 72, 9881; (c) Smith, C. et al.
PCT Patent Application Publication No. WO 2005/028483. [0115]
.sup.v (a) Madyashtha, K. M. et al. Proc. Indian Acad. Sci. 1984,
106, 1203; (b) Madyastha, K. M. et al. J. Chem. Soc. Perkin Trans.
1, 1994, 911. [0116] .sup.vi Chaudhary, V. et al. Collect. Czech.
Chem. Commun. 2009, 74, 1179. [0117] .sup.vii (a) Carroll, R. J. et
al. Adv. Synth. Catal. 2008, 350, 2984; (b) Carroll, R. J. et al.
U. S. Patent Application Publication No. US 2009/0005565. [0118]
.sup.viii References for the formation of oxymorphone from
oripavine: Dung et al. U.S. Pat. No. 7,851,482; Huang, US
20080125592, US 20100274019, US 20110009634; Wang et al. US
20100113787. References for the formation of oxymorphone from
thebaine via 14-hydroxycodeinone: Weiss et al. J. Org. Chem. 1957,
22, 1505-8. [0119] .sup.ix (a) Pillai, O.; Hamad, M. O.; Crooks, P.
A.; Stinchcomb, A. L. Pharm. Res., 2004, 21, 1146; (b) Hamad, M.
O.; Kiptoo, P. K.; Stinchcomb, A. L.; Crooks, P. A.; Bioorg. Med.
Chem. 2006, 14, 7051
* * * * *